Retinol binding protein 4 (hereinafter sometimes to be abbreviated as “RBP4”) is known to be a sole blood retinol transport protein mainly produced in the liver. In recent years, moreover, RBP4 is suggested to be an insulin resistance-inducing factor from the following literatures and the like.
(1) Since RBP4 expression increases in the adipocytes of GLUT4 knockout mouse showing insulin resistance, RBP4 is suggested to be a potential adipocytokine inducing insulin resistance (see Nature 436, 356-362 (2005)).
(2) It has been reported that RBP4 overexpression mouse shows hyperglycemia and hyperinsulinemia, and RBP4 knockout mouse shows promotion of glucose tolerance and insulin sensitivity as phenotype (see Nature 436, 356-362 (2005)).
(3) It has been reported that mouse bred on a high-fat diet shows high blood RBP4 value, which is correlated with induction of insulin resistance (see Nature 436, 356-362 (2005)).
(4) It has been reported that disease model mouse showing diabetes and/or obesity pathology such as ob/ob mouse, 11β-HSD1 overexpression (adipose tissue specific) mouse, MC4R knockout mouse, GLUT4 knockout (adipose tissue•skeletal muscle specific) mouse and the like also shows high blood RBP4 value (see Nature 436, 356-362 (2005)).(5) It has been reported that blood RBP4 concentration and insulin sensitivity and/or sugar disposal rate are inversely correlated in human. It has also been reported that the glucose infusion rate decreases as the blood RBP4 concentration increases in euglycemic hyperinsulinemic glucose clamp test (see Cell Metab., 6, 79-87 (2007)).(6) While exercise is known to improve insulin sensitivity, an extremely high correlation between such an improving effect and lowering of blood RBP4 concentration has been reported recently (see N. Engl. J. Med., 354, 2552-2563 (2006)).(7) WO2005-059564 describes that a compound that controls RBP4 activity is useful for the treatment of insulin resistance.
All these suggest that a compound capable of lowering blood RBP4 concentration can be a therapeutic drug for diabetes.
RBP4 is stably present in blood in the form of a complex resulting from the binding of retinol and TTR (transthyretin). When RBP4 is dissociated from TTR and becomes free, it is decomposed in and excreted from the kidney comparatively rapidly. It is unknown whether the binding of RBP4 and retinol is indeed essential for the formation of a complex with TTR. However, fenretinide, a retinol derivative, inhibits the binding of RBP4 and retinol, and consequently inhibits formation of a complex with TTR. It is known that administration of fenretinide to animal induces lowering of blood RBP4 (see Biochim. Biophys. Acta, 1294, 48-54 (1996)).
From the foregoing findings, a compound that inhibits formation of a complex of RBP4 and TTR by inhibiting the binding of RBP4 and retinol is expected to lower blood RBP4 concentration and consequently induce correction of hyperglycemia and improvement of insulin resistance.
In recent years, moreover, a report has documented that blood RBP4 value and blood TG (triglyceride) or LDL cholesterol value positively correlate in human, and blood RBP4 value negatively correlates with HDL cholesterol value (see J. Atheroscler. Thromb., 13, 209-215 (2006), N. Engl. J. Med., 355, 1392-1395 (2006), Diabetes, 56 (Supplement 1), A378 (1477-P) (2007)), thus suggesting relationship with lipid metabolism.
It has been reported the link between RBP4 and eye disease. For example, excess vitamin-A levels in target organs and tissues, such as the eye, may cause a variety of retinal diseases, including macular degeneration, and lowering RBP4 is effective to prevent or treat these eye diseases (see WO2009/042444).
Fenretinide is studied in patients with geographic atrophy (GA), the most advanced form of dry age-related macular degeneration (AMD). Fenretinide is suggested to halt the accumulation of retinol (vitamin A) toxin through affinity to RBP4. It is hypothesized that to slow the formation and accumulation of toxic byproducts, A2E (bis-retinoid pyridinium) for example, thought to be responsible for vision loss in condition such as GA. Sirion Therapeutics, Inc. has announced positive results from analysis of phase II trial evaluating fenretinide for the treatment of GA associated with AMD.
In view of the above, a pharmaceutical agent having an action to lower blood RBP4 value (concentration) (also referred to as “RBP4 lowering action” in the present specification) (also referred to as “RBP4 lowering agent” (agent for reducing RBP4) in the present specification) is expected to be widely applicable to lifestyle-related diseases.
WO02/068406 discloses that compounds such as a compound represented by the following formula has an inhibitory effect on VEGF and applications for preventing or treating of retinol-related diseases, cancer, diabetes and the like:
wherein A1 and A2 are each independently C, CH or N; ring A is a 5- or 6-membered partially saturated heterocycle, a 5- or 6-membered aromatic heterocycle and the like; X is
Z is O or S; R is an optionally substituted 4- to 6-membered heterocyclic group, a substituted aromatic ring group and the like; and R1 is an optionally substituted 6- to 10-membered aromatic ring group, an optionally substituted 4- to 6-membered aromatic heterocyclic group and the like.
WO2004/007481 discloses that compounds such as a compound represented by the following formula has an inhibitory effect on VEGF and applications for preventing or treating of retinol-related diseases, cancer, diabetes and the like:
wherein R is an optionally substituted 6-indazolyl group, an optionally substituted 1-oxo-2,3-dihydro-1H-isoindol-4-yl group, an optionally substituted 2-oxo-2,3-dihydro-1H-benzimidazol-5-yl group or an optionally substituted 4-oxo-3,4-dihydroquinazolin-6-yl group; and R1 is an optionally substituted aromatic ring group, optionally substituted 5- or 6-membered aromatic heterocyclic group and the like.
J. Biol. Chem., January 2009, vol. 284, p. 7673-7680 as Manuscript M809654200 discloses a compound represented by the following formula has a lowering effect on RBP4:

WO2009/042444 discloses that compounds such as a compound represented by the following formula has a lowering effect on RBP4 and applications for preventing or treating of retinol-related diseases, diabetes and the like:
wherein A is O, NH, or S; B is a bond, —(C2-C7)alkyl, —(C2-C7)alkenyl, —(C3-C8)cycloalkyl, —(C2-C7)heteroalkyl, —(C3-C8)heterocycloalkyl, —(C3-C8)cycloalkenyl, or —(C3-C8)heterocycloalkenyl; D is isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, sec-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl; E is (C═O)—OR, —O—(C═O)—R, —(C═O)—R, —OR, a carboxylic acid bioisostere, —(C═O)—NR1R, (C═O)—R, —(C1-C7)alkyl-(C═O)—OR, or —(C1-C7)alkyl-(C═O)—NR1R;R is H or
G is —OR1, —(C1-C6)alkyl, —(C1-C6)alkyl-OR1, halogen, —CO2R1, —(C1-C6)alkyl-CO2R1, NHR1, —(C1-C6)alkyl-NHR1, —(C═O)NHR1, —(C1-C6)alkyl-(C═O)NHR1, —NHR1(C═O)R1 or —(C1-C6)alkyl-NHR1(C═O)R1; R1 is H or (C1-C6)alkyl; X is a halogen; or an active metabolite, or a pharmaceutically acceptable prodrug, salt, or solvate thereof; and a pharmaceutically acceptable excipient.
WO2009/051244 discloses that a compound represented by the following formula has a lowering effect on RBP4 and is useful for preventing or treating of diabetes and the like:
wherein ring A is benzene optionally further substituted; R1 is an optionally substituted branched C3-6 alkyl group; X1 is O, S, SO, SO2 or NH; X2 is a bond or a C1-3 alkylene group; ring B is azetidine, pyrrolidine or piperidine; X3 is CO or SO2; R2 is a substituent; provided that(1) when —X1—X2— is —NH— and ring B is piperidine, then X3 is CO; or(2) when X3 is CO, then R2 is not a tert-butoxy group, or a salt thereof.
WO2009/145286 discloses that a compound represented by the following formula has a lowering effect on RBP4 and is useful for preventing or treating of diabetes and the like:
wherein ring A is a 5-membered nonaromatic heterocyclic optionally further substituted with a substituent, ring B is an optionally further substituted benzene ring, and X is a bond, O, CH2O, OCH2, CH2, (CH2)2, S, CH2S, SCH2, S(O), CH2S(O), S(O)CH2, S(O)2, CH2S(O)2, or S(O)2CH2, with the proviso that {(3S,5R)-1-[4-(trifluoromethyl)benzyl]-5-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}acetate, {(3S,5R)-1-[2,5-bis(trifluoromethyl)benzyl]-5-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}acetate, {4-oxo-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-5-yl}acetate, {2-oxo-1-[3-(trifluoromethyl)phenyl]pyrrolidine-3-yl}acetate, {3-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-1,3-oxazolidine-5-yl}acetate, {4-oxo-3-[3-(trifluoromethyl)phenyl]-1,3-oxazolidine-5-yl}acetate, {3-[2-chloro-5-(trifluoromethyl)phenyl]-4-oxo-1,3-thiazolidine-5-yl}acetate, and {5-oxo-1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1H-pyrazole-3-yl}acetate is excluded, or the salt thereof.